Survey Report: Many Doctors Stand by Ezetimibe (Zetia)

A sizeable minority of doctors continues to believe that ezetimibe (Zetia) is a powerful agent for their patients, according to a MedPage Today poll.

Debate over data from the ENHANCE study -- which found that ezetimibe/simvastatin (Vytorin) did not slow atherosclerosis as measured by carotid intima-media thickness -- has embroiled the medical community in a debate over ezetimibe since the preliminary results were released in January.

The complete findings were reported earlier this month at the American College of Cardiology meeting in Chicago and published simultaneously online in the New England Journal of Medicine.

But, although the trial found no significant reductions in the primary endpoint, the combination did produce a significantly greater decrease in LDLs -- a 58% reduction compared with a 42% reduction for patients taking simvastatin alone.

To gauge where physicians on the front lines come down on the issue, MedPage Today asked readers whether, on the basis of the data, ezetimibe should be considered an agent of last resort.

The answer was anything but definitive: 56% of the 340 respondents said Yes, but 44% said No.

Reasoning behind the votes showed engagement with the issue, and a willingness to take on the experts.

Said one physician: "The presenter at ACC was biased . . . It will be shown in other studies that the "evidence-based" results of Lipitor and Crestor, in fact, did not show regresssion after two years. Furthermore, the indicators of LDL lowering and C-reactive protein were huge in the ENHANCE and every other study. History will show that ezetimibe will be life changing and heart protecting. The lipid societies support my view and the ACC needs to take a leadership role and make a statement."

Another referred to the study population, noting that the patients in the ENHANCE study had familial hypercholesterolemia with baseline LDLs of around 300. "These are very difficult-to-treat patients," she said, "and these results may not be applicable to other patients. We need outcome studies with ezetimibe to know. All we do know is that it lowers LDL."

A colleague who pointed to those same issues noted that no broad generalizations can be made based on ENHANCE.

One doctor put it simply. "Ezetimibe (Zetia) is approved by the FDA as an adjunct to diet in the lowering of LDL and cholesterol."

For some physicians the data are clear, and point to the effectiveness of ezetimibe in lowering LDL.

"What is so hard to understand?" said one physician seemingly exasperated by the debate. "To benefically impact coronary artery disease as well as peripheral vascular disease, we need to get the LDL down. While statins pushed to higher levels may eventually bring down both the total cholesterol and sometimes the LDL, we know that when you add Zetia, both come down to target levels."

"Other than the fact that in the type of patients involved in the ENHANCE study there was little effect in the plaque formation," he continued, "what is there to indicate that we should not use it in the ordinary hyperlipidemic patient. It is effective and it works to get us to the target levels that we are attempting to get to. Again, what is so hard to understand?"

Said another respondent, "Plaque regression has never been reported in populations that were unable to acheive an LDL less than 70. Having said that, Zetia should be used in the patient who is unable to lower LDL to goal with maximally tolerated therapy. ENHANCE should not be used as an excuse to not pursue better triglyceride or HDL levels."

One cardiologist pointed to the National Lipid Association for guidance, noting that the organization stresses the importance of getting patients to low-density lipoprotein cholesterol treatment targets as identified in the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) guidelines.

"Lowered levels of LDL-C are associated with corresponding reductions in cardiovascular disease risk," he said, "as has been demonstrated in studies of both primary and secondary prevention. Nothing in this study has changed our position about the necessity for lipid lowering or the need to treat patients to established NCEP goals."

Not all respondents kept the discussion to the science, though. Said one: "These patients were not 'run-of-the-mill' because the company figured that they would not be able to demonstrate an effect in 'run-of-the-mill' patients. This is a common way to market a new drug in the absence of relevant endpoints in a relevant population. They still failed anyway, and then they suppressed the results. We're still supposed to endorse their products to our patients?"

Second, he continued, "to all those who plan to take the drug because your labs look better or are 'at target': As a clinician, I have to treat YOU, not your labs. Until Vytorin proves it has some benefit -- any benefit -- to you, I'm not going to waste your money cleaning up your labs. I'm certainly not going to lower your statin dose (proven benefit on clinical outcomes) in order to introduce this unproven drug."

Finally, one respondent did what many researchers do in the reporting their studies -- call for more study.

Said he: "If the data in this study are reflected in events and, as Dr. [Steven] Nissen noted, the markers were pointed in the wrong direction, would that not be evidence to cause a rethinking of the way statins work?

"Statins do other beneficial things beside LDL reduction," he added. "Should a study not be done to see what is really causing the benefit. It is possible that the major benefit of statins is in these other effects. If that is true then lipid guidelines are targeting the wrong parameter and different statins may, in fact, cause different outcomes while having the same effect on lipids."

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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